Phosphodiesterase (PDE) is an enzyme that play an important role in the process of degrading and inactivating cyclic nucleotides (cAMP or cGMP), which are important second messengers. PDE degrading cAMP is classified into some isozymes, among which type 4 PDE (PDE4) is a primary cAMP-degrading enzyme present in many inflammatory cells and immunocytes (see Non Patent Literature 1: Expert Opin. Investig. Drugs, 11, 1-13, 2002).
PDE4 inhibitors are known to be useful in the treatment of various inflammatory diseases in which TNF-α or the like is involved, because of suppressing the production or release of various cytokines, such as TNF-α, which play an important role in inflammation cascades (see Non Patent Literature 1: Expert Opin. Investig. Drugs, 11, 1-13, 2002). Also, it has been reported that PDE4 inhibitors exhibit effects on not only inflammation in the respiratory system but also inflammation in the skin, and additionally, it has been reported that they also exhibit effects on mental illness (see Non Patent Literature 1: Expert Opin. Investig. Drugs, 11, 1-13, 2002).
Theophylline known as a PDE inhibitor has heretofore been used in the treatment of asthma (see Non Patent Literature 2: British Journal of Pharmacology, 155, 308-315, 2008). In recent years, roflumilast, which is a potent PDE4 inhibitor, has been approved and used as a therapeutic drug for chronic obstructive pulmonary disease (COPD) in Europe and the United States (see Non Patent Literature 3: British Journal of Pharmacology, 163, 53-67, 2011), and additionally, the efficacy for interstitial pneumonia (idiopathic pulmonary fibrosis, etc.) in animal models has also been suggested (see Non Patent Literature 4: British Journal of Pharmacology, 156, 534-544, 2009). Moreover, it has been reported that apremilast, which is a PDE inhibitor, is effective for psoriatic arthritis and psoriasis vulgaris in clinical trials (see Non Patent Literature 5: Amadeu G and Richard S. R., Expert Opin. Ther. Patents, August 2013, Vol. 23, No. 8, 997-1016). In addition, clinical trials of PDE4 inhibitors for various inflammatory diseases (inflammatory bowel disease, Crohn's disease, multiple sclerosis, rheumatism, atopic dermatitis and sarcoidosis) have been carried out, and additionally, their possibilities for systemic lupus erythematosus have also been pointed out in nonclinical trials (see Non Patent Literature 1: Expert Opin. Investig. Drugs, 11, 1-13, 2002, and Non Patent Literature 6: BMC Medicine, 11, 96, 2013). Furthermore, among PDE4 inhibitors, there are many compounds having central effects, and there have also been reports on effects on depression, Parkinson's disease, learning and memory disorders and Alzheimer's disease (see Non Patent Literature 1: Expert Opin. Investig. Drugs, 11, 1-13, 2002, and Non Patent Literature 6: BMC Medicine, 11, 96, 2013). Examples of diseases on which PDE4 inhibitors are likely to exhibit effects as described above include asthma, COPD, interstitial pneumonia, inflammatory bowel disease, Crohn's disease, multiple sclerosis, rheumatism, atopic dermatitis, psoriatic arthritis, psoriasis vulgaris, sarcoidosis, systemic lupus erythematosus, depression, learning and memory disorders, Parkinson's disease and Alzheimer's disease.
Moreover, although the activity against serotonin 5-HT3 of a compound having a structure similar to that of a benzoxazole derivative, which is the active ingredient of the present invention, is described in Patent Literature 1 (JP 6-345744 A), Patent Literature 2 (JP 10-29987 A), etc., there is no description about having PDE4 inhibitory activity.